Structure and mechanism of the mitochondrial calcium transporter NCLX
As a key mitochondrial Ca<sup>2+</sup> transporter, NCLX regulates intracellular Ca<sup>2+</sup> signalling and vital mitochondrial processes<sup>1-3</sup>. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction<sup>4-9</sup>. Despite substantial advances in the field, the transport mechanisms of NCLX remain unclear. Here we report the cryo-electron microscopy structures of NCLX, revealing its architecture, assembly, major conformational states and a previously undescribed mechanism for alternating access. Functional analyses further reveal an unexpected transport function of NCLX as a H<sup>+</sup>/Ca<sup>2+</sup> exchanger, rather than as a Na<sup>+</sup>/Ca<sup>2+</sup> exchanger as widely believed<sup>1</sup>. These findings provide critical insights into mitochondrial Ca<sup>2+</sup> homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca<sup>2+</sup>.
Authors
- Deniz Aydın (ORCID: https://orcid.org/0000-0002-2758-2480)
- Minrui Fan (ORCID: https://orcid.org/0009-0002-8375-6972)
- Jianxiu Zhang (ORCID: https://orcid.org/0000-0002-1864-7510)
- Andrew H. Reiter (ORCID: https://orcid.org/0000-0003-1406-4913)
- Briana L. Sobecks (ORCID: https://orcid.org/0000-0003-2086-8598)
- Jinru Zhang (ORCID: https://orcid.org/0000-0001-5706-9031)
- Ming-Feng Tsai (ORCID: https://orcid.org/0000-0003-4277-1885)
- Chen-Wei Tsai (ORCID: https://orcid.org/0009-0000-2469-8966)
- Madison Rodriguez (ORCID: https://orcid.org/0000-0001-7000-5462)
- Ron O. Dror (ORCID: https://orcid.org/0000-0002-6418-2793)
- Siyuan Du (ORCID: https://orcid.org/0000-0001-5215-0535)
- Aswini R. Krishnan (ORCID: https://orcid.org/0000-0003-0764-5111)
- Carolyn R. Bertozzi (ORCID: https://orcid.org/0000-0003-4482-2754)
- Liang Feng (ORCID: https://orcid.org/0000-0001-6171-2050)
- Tsung‐Yun Liu
- Yu-Lun Huang (ORCID: https://orcid.org/0000-0002-0546-4512)
Institutions
- Stanford Health Care (US)
- Stanford Medicine (US)
- University of Virginia (US)
- University of Colorado Anschutz Medical Campus (US)
- Stanford University (US)
Publication Details
- Journal
- Nature
- Published
- 2025-09-10
- DOI
- https://doi.org/10.1038/s41586-025-09491-0
- Citations
- 6
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 4.84